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1.
J Bone Miner Res ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633122

RESUMO

The possible mechanisms underlying the quantitative and qualitative effects of cinacalcet on bone were explored in a chronic kidney disease-mineral and bone disorder (CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation. Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (µCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose cinacalcet treatment. In vitro studies revealed that cinacalcet inhibited receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of caspase-related apoptosis, reversal of OC autophagy through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway. Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and Mineral Research (ASBMR).

2.
Int J Mol Sci ; 22(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34681927

RESUMO

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

3.
Indian J Orthop ; 55(Suppl 2): 409-417, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34306555

RESUMO

Background: In female badminton players, certain landings are associated with injury to the anterior cruciate ligament (ACL). However, the kinematic and kinetic changes of the landing leg and the effects of risky posture on ACL injuries among female vs male badminton players are still unknown. We hypothesized that female players land with a significantly higher knee valgus angle and moment compared to male players during single-leg landings in badminton. Methods: Ten male and ten female badminton players were enrolled in this study. In the laboratory, these subjects performed back-stepping to the backhand side with a concurrent overhead stroke, a single-leg landing on the force plate, and a return to the starting position. The kinematic data in the stance phase were normalized ranging from 0% as initial contact to 100% as toe-off; and 0% as initial contact to 100% as maximum knee flexion in the impact phase. Results: The knee valgus angle in female players was significantly higher in initial contact (5.06° ± 6.83° vs - 5.10° ± 4.30, p = .001) and maximal knee valgus angle (7.58° ± 9.54° vs - 3.93° ± 4.22°, p = .004) compared to male players. The knee valgus moment was significantly higher in male players than female players ( - 0.09 ± 0.12 vs 0.03 ± 0.10 N∙m/kg, p = .032) in initial contact during the impact phase. During landings, female badminton players had lower hip flexion angles, greater knee valgus angles, and greater ankle dorsiflexion angles. Conclusion: Female badminton players presented higher knee valgus angles but smaller knee valgus moments compared with male players during backward single-leg landings. The concomitant kinematic and kinetic changes of the hip, knee, and ankle joints also can play an important role in the higher incidence of ACL injury in female athletes. Supplementary Information: The online version contains supplementary material available at 10.1007/s43465-021-00421-6.

4.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298988

RESUMO

This study evaluated the biocompatibility and biological performance of novel additive-manufactured bioabsorbable iron-based porous suture anchors (iron_SAs). Two types of bioabsorbable iron_SAs, with double- and triple-helical structures (iron_SA_2_helix and iron_SA_3_helix, respectively), were compared with the synthetic polymer-based bioabsorbable suture anchor (polymer_SAs). An in vitro mechanical test, MTT assay, and scanning electron microscope (SEM) analysis were performed. An in vivo animal study was also performed. The three types of suture anchors were randomly implanted in the outer cortex of the lateral femoral condyle. The ultimate in vitro pullout strength of the iron_SA_3_helix group was significantly higher than the iron_SA_2_helix and polymer_SA groups. The MTT assay findings demonstrated no significant cytotoxicity, and the SEM analysis showed cells attachment on implant surface. The ultimate failure load of the iron_SA_3_helix group was significantly higher than that of the polymer_SA group. The micro-CT analysis indicated the iron_SA_3_helix group showed a higher bone volume fraction (BV/TV) after surgery. Moreover, both iron SAs underwent degradation with time. Iron_SAs with triple-helical threads and a porous structure demonstrated better mechanical strength and high biocompatibility after short-term implantation. The combined advantages of the mechanical superiority of the iron metal and the possibility of absorption after implantation make the iron_SA a suitable candidate for further development.


Assuntos
Implantes Absorvíveis , Materiais Biocompatíveis , Âncoras de Sutura , Alanina Transaminase/sangue , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Fenômenos Biomecânicos , Nitrogênio da Ureia Sanguínea , Fosfatos de Cálcio/química , Fosfatos de Cálcio/toxicidade , Sulfato de Cálcio/administração & dosagem , Sulfato de Cálcio/química , Sulfato de Cálcio/toxicidade , Creatinina/sangue , Desenho de Equipamento , Fêmur/diagnóstico por imagem , Fêmur/ultraestrutura , Ferro , Lasers , Teste de Materiais , Microscopia Eletrônica de Varredura , Estrutura Molecular , Osseointegração , Polímeros/química , Polímeros/toxicidade , Porosidade , Coelhos , Distribuição Aleatória , Resistência à Tração , Vísceras , Microtomografia por Raio-X
5.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065735

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.


Assuntos
Imunidade Adaptativa , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Vitamina D/metabolismo , Vitamina D/farmacologia , COVID-19/mortalidade , COVID-19/fisiopatologia , COVID-19/virologia , Síndrome da Liberação de Citocina/complicações , Citocinas/metabolismo , Humanos , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/fisiologia
6.
Int J Med Sci ; 18(2): 314-324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390800

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is the largest health crisis ever faced worldwide. It has resulted in great health and economic costs because no effective treatment is currently available. Since infected persons vary in presentation from healthy asymptomatic mild symptoms to those who need intensive care support and eventually succumb to the disease, this illness is considered to depend primarily on individual immunity. Demographic distribution and disease severity in several regions of the world vary; therefore, it is believed that natural inherent immunity provided through dietary sources and traditional medicines could play an important role in infection prevention and disease progression. People can boost their immunity to prevent them from infection after COVID-19 exposure and can reduce their inflammatory reactions to protect their organ deterioration in case suffering from the disease. Some drugs with in-situ immunomodulatory and anti-inflammatory activity are also identified as adjunctive therapy in the COVID-19 era. This review discusses the importance of COVID-19 interactions with immune cells and inflammatory cells; and further emphasizes the possible pathways related with traditional herbs, medications and nutritional products. We believe that such pathophysiological pathway approach treatment is rational and important for future development of new therapeutic agents for prevention or cure of COVID-19 infection.


Assuntos
COVID-19/tratamento farmacológico , Interações Hospedeiro-Patógeno , Medicina Tradicional , COVID-19/prevenção & controle , COVID-19/virologia , Quimioterapia Combinada , Humanos , Imunomodulação , Terapia de Alvo Molecular , Fitoterapia , Extratos Vegetais/uso terapêutico , SARS-CoV-2/fisiologia , Vitaminas/uso terapêutico , Zinco/uso terapêutico
7.
Toxins (Basel) ; 12(11)2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138205

RESUMO

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-ß1 (TGF-ß1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-ß1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.


Assuntos
Indicã/toxicidade , Insuficiência Renal Crônica/etiologia , Toxinas Biológicas/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fator de Crescimento Transformador beta1/metabolismo
8.
Int J Mol Sci ; 21(20)2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33050571

RESUMO

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 µM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.


Assuntos
Indicã/efeitos adversos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Substâncias Protetoras/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Biológicos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese , Fosforilação , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
9.
J Orthop Surg Res ; 15(1): 419, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938491

RESUMO

BACKGROUND: Distal radius fracture (DRF) is the most common upper extremity fracture that requires surgery. Operative treatment with a volar locking plate has proved to be the treatment of choice for unstable fractures. However, no consensus has been reached about the benefits of pronator quadratus (PQ) repair after volar plate fixation of DRF in terms of patient-reported outcome measures, pronation strength, and wrist mobility. METHODS: We searched the PubMed, Embase, Cochrane Central, and China National Knowledge Infrastructure (CNKI) databases up to March 13, 2020, and included randomized-controlled, non-randomized controlled, or case-control cohort studies that compared cases with and without PQ repair after volar plate fixation of DRF. We used a random-effects model to pool effect sizes, which were expressed as standardized mean differences (SMDs) and 95% confidence intervals. The primary outcomes included Disabilities of the Arm, Shoulder, and Hand scores and pronation strength. The secondary outcomes included the SMDs in pain scale score, wrist mobility, and grip strength. The outcomes measured were assessed for publication bias by using a funnel plot and the Egger regression test. RESULTS: Five randomized controlled studies and six retrospective case-control studies were included in the meta-analysis. We found no significant difference in primary and secondary outcomes at a minimum of 6-month follow-up. In a subgroup analysis, the pronation strength in the PQ repair group for AO type B DRFs (SMD = - 0.94; 95% CI, - 1.54 to - 0.34; p < 0.01) favored PQ repair, whereas that in the PQ repair group for non-AO type B DRFs (SMD = 0.39; 95% CI, 0.07-0.70; p = 0.02) favored no PQ repair. DISCUSSION: We found no functional benefit of PQ repair after volar plate fixation of DRF on the basis of the present evidence. However, PQ muscle repair showed different effects on pronation strength in different groups of DRFs. Future studies are needed to confirm the relationship between PQ repair and pronation strength among different patterns of DRF. REGISTRATION: This study was registered in the PROSPERO registry under registration ID No. CRD42020188343 . LEVEL OF EVIDENCE: Therapeutic III.


Assuntos
Placas Ósseas , Antebraço , Fixação Interna de Fraturas/métodos , Fraturas não Consolidadas/cirurgia , Músculo Esquelético/cirurgia , Fraturas do Rádio/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Músculo Esquelético/fisiopatologia , Avaliação de Resultados da Assistência ao Paciente , Pronação , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
10.
Int J Mol Sci ; 21(17)2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32878067

RESUMO

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)-produced in the liver by colonic microorganisms-cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)-a gut microbe-dependent metabolite of dietary L-carnitine and choline-is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD.


Assuntos
Antioxidantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Resveratrol/uso terapêutico , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Humanos , Fatores de Risco
11.
J Orthop Surg (Hong Kong) ; 28(2): 2309499020935994, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730729

RESUMO

Reconstruction of an infected knee joint with a large defect and extensor mechanism deficiency is challenging. In this study, we aim to describe a one-stage reconstruction surgery and provide its surgical outcome. Two patients had patellar open fracture and subsequent septic arthritis; in addition, a large soft tissue defect, loss of patella, and shortening of the patellar tendon were observed. The semitendinosus-gracilis tendon formed a loop to stabilize the patella. A free or supercharged reverse pedicle myocutaneous anterolateral thigh flap with fascial extension is designed to fill the defect and eradicate the infection. Mean clinical follow-up was 18 months. Although some limitation in the knee range of motion was observed, the dynamometer showed only partial loss in peak concentric power and eccentric power. We developed an innovative surgical procedure to alleviate infection and reconstruct a complex knee defect with extensor mechanism deficiency; this procedure resulted in favorable clinical outcomes.


Assuntos
Tendões dos Músculos Isquiotibiais/transplante , Traumatismos do Joelho/cirurgia , Articulação do Joelho/cirurgia , Ligamento Patelar/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Retalhos Cirúrgicos , Adulto , Feminino , Humanos , Traumatismos do Joelho/fisiopatologia , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Transplante Autólogo
12.
Tech Hand Up Extrem Surg ; 25(2): 63-68, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32694408

RESUMO

Several fingertip reconstruction options exist, among which, the use of a volar advancement flap or local transposition flap is a simple and effective technique for reconstructing the volar pulp with the same skin texture. To advance the flap, we have to release the tethering structure and sometimes include the neural branches. We describe a concept of an all neural branch-preserving technique to harvest a volar flap. We demonstrate this technique on an anatomic specimen and 1 case with delicate surgical tips. We performed this technique in 16 patients, and the mean follow-up period was 28.4 months. The mean range of motion of the distal interphalangeal joint was 70.3 degrees, and that of the proximal interphalangeal joint was 101.9 degrees. The mean static 2-point discrimination of the volar pulp was 4.8 mm. This technique could be applied on the volar advancement flap with a better sensation recovery.

13.
Clin Rehabil ; 34(9): 1217-1229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32539454

RESUMO

OBJECTIVE: To compare the efficacy of various strategies in the treatment of trigger finger. DATA SOURCES: A systematic literature search for randomized controlled trials to compare treatments for trigger finger was conducted through three online databases, Pubmed, Embase and Cochrane Library, from their inception dates to 22 May 2020. METHODS: Relative risk (RR) with 95% confidence interval (CI) was used to evaluate the effect sizes in success rate for included articles. RESULTS: Sixteen articles (n = 1185) were included in our meta-analysis. The results showed that the efficacy of steroid injection was significantly better than the placebo group at short-term follow-ups (RR = 19.00, 95% CI = 1.17-309.77 for one-week; RR = 3.70, 95% CI = 3.70, 95% CI = 1.61-8.53 for one-month), and then became non-significant at four months (RR = 3.21, 95% CI = 0.88-11.79). There was no significant difference in success rate between steroid injection and nonsteroidal anti-inflammatory drug injection, and between open surgery and percutaneous release at all the follow-ups. Only surgical treatment had significantly better efficacy in success rate than steroid injection at all follow-ups (RR = 0.48, 95% CI = 0.34-0.66 for one-month; RR = 0.87, 95% CI = 0.80-0.96 for three-month; RR = 0.58, 95% CI = 0.48-0.68 for six-month; RR = 0.38, 95% CI = 0.20-0.72 for 12-month). CONCLUSION: There were no differences in efficacy between steroid injection and shockwave or nonsteroidal anti-inflammatory drug injection. The surgical treatments had the best efficacy among these treatments.


Assuntos
Dedo em Gatilho/terapia , Humanos
14.
Int J Mol Sci ; 21(10)2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32429048

RESUMO

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Indicã/toxicidade , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Camundongos , Osteoclastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação
15.
Int J Mol Sci ; 21(7)2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32252330

RESUMO

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Células-Tronco Mesenquimais/metabolismo , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Vitamina D/metabolismo , Animais , Biomarcadores , Gerenciamento Clínico , Suscetibilidade a Doenças , Células Progenitoras Endoteliais/efeitos dos fármacos , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/patologia , Vitamina D/farmacologia , Vitamina D/uso terapêutico
16.
Int J Mol Sci ; 21(5)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32111067

RESUMO

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of ß-catenin that, following the facilitation of ß-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.


Assuntos
Sirtuína 1/metabolismo , Calcificação Vascular/metabolismo , Adipocinas , Tecido Adiposo/metabolismo , Animais , Apoptose , Doenças Cardiovasculares/metabolismo , Transdiferenciação Celular , Células Endoteliais/metabolismo , Proteína Forkhead Box O1/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Osteogênese/fisiologia , Fatores de Transcrição , Calcificação Vascular/prevenção & controle , Rigidez Vascular , beta Catenina/metabolismo
18.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181716

RESUMO

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/ß-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.


Assuntos
Reabsorção Óssea/metabolismo , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Cinacalcete/farmacologia , Osteoclastos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Proteínas Wnt/metabolismo , Animais , Densidade Óssea , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Células Cultivadas , Cinacalcete/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo
20.
Nutrients ; 11(1)2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30642029

RESUMO

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).


Assuntos
Insuficiência Renal Crônica/tratamento farmacológico , Calcificação Vascular/tratamento farmacológico , Vitamina D/farmacologia , Vitamina K/farmacologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Suplementos Nutricionais , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/tratamento farmacológico , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/tratamento farmacológico
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